Combination therapy for type II diabetes or syndrome X

ABSTRACT

This invention provides methods of using a pharmacological combination of a biguanide agents, such as metformin, and one or more PTPase inhibiting agents and, optionally, one or more sulfonlylurea agents, including glyburide, glyburide, glipizide, glimepiride, chlorpropamide, tolbutamide, or tolazamide, for treatment in a mammal of Syndrome X, type II diabetes or metabolic disorders mediated by insulin resistance or hyperglycemia. Further included in this invention is a method of modulating blood glucose levels in a mammal utilizing the combination of one or more PTPase inhibiting agents and one or more sulfonlylurea agents.

[0001] This application claims priority from copending provisionalapplication Serial No. 60/296,502, filed Jun. 7, 2001, the entiredisclosure of which is hereby incorporated by reference.

[0002] This invention relates to pharmaceutical combinations of PTPaseinhibiting compounds, a biguanide agent and, optionally, a sulfonylureaagent. Particularly, this invention concerns methods of treating orinhibiting type II diabetes or Syndrome X and related conditions in amammal in need of such treatment utilizing combinations of these classesof pharmacological agents.

BACKGROUND OF THE INVENTION

[0003] The prevalence of insulin resistance in glucose intolerantsubjects has long been recognized. Reaven et al (American Journal ofMedicine 1976, 60, 80) used a continuous infusion of glucose and insulin(insulin/glucose clamp technique) and oral glucose tolerance tests todemonstrate that insulin resistance existed in a diverse group ofnonobese, nonketotic subjects. These subjects ranged from borderlineglucose tolerant to overt, fasting hyperglycemia. The diabetic groups inthese studies included both insulin dependent (IDDM) and noninsulindependent (NIDDM) subjects.

[0004] Coincident with sustained insulin resistance is the more easilydetermined hyperinsulinemia, which can be measured by accuratedetermination of circulating plasma insulin concentration in the plasmaof subjects. Hyperinsulinemia can be present as a result of insulinresistance, such as is in obese and/or diabetic (NIDDM) subjects and/orglucose intolerant subjects, or in IDDM subjects, as a consequence ofover injection of insulin compared with normal physiological release ofthe hormone by the endocrine pancreas.

[0005] The association of hyperinsulinemia with obesity and withischemic diseases of the large blood vessels (e.g. atherosclerosis) hasbeen well established by numerous experimental, clinical andepidemiological studies (summarized by Stout, Metabolism 1985, 34, 7,and in more detail by Pyorala et al, Diabetes/Metabolism Reviews 1987,3, 463). Statistically significant plasma insulin elevations at 1 and 2hours after oral glucose load correlates with an increased risk ofcoronary heart disease.

[0006] Since most of these studies actually excluded diabetic subjects,data relating the risk of atherosclerotic diseases to the diabeticcondition are not as numerous, but point in the same direction as fornondiabetic subjects (Pyorala et al). However, the incidence ofatherosclerotic diseases in morbidity and mortality statistics in thediabetic population exceeds that of the nondiabetic population (Pyoralaet al; Jarrett Diabetes/Metabolism Reviews 1989,5, 547; Harris et al,Mortality from diabetes, in Diabetes in America 1985).

[0007] The independent risk factors obesity and hypertension foratherosclerotic diseases are also associated with insulin resistance.Using a combination of insulin/glucose clamps, tracer glucose infusionand indirect calorimetry, it has been demonstrated that the insulinresistance of essential hypertension is located in peripheral tissues(principally muscle) and correlates directly with the severity ofhypertension (DeFronzo and Ferrannini, Diabetes Care 1991, 14, 173). Inhypertension of the obese, insulin resistance generateshyperinsulinemia, which is recruited as a mechanism to limit furtherweight gain via thermogenesis, but insulin also increases renal sodiumreabsorption and stimulates the sympathetic nervous system in kidneys,heart, and vasculature, creating hypertension.

[0008] It is now appreciated that insulin resistance is usually theresult of a defect in the insulin receptor signaling system, at a sitepost binding of insulin to the receptor. Accumulated scientific evidencedemonstrating insulin resistance in the major tissues which respond toinsulin (muscle, liver, adipose), strongly suggests that a defect ininsulin signal transduction resides at an early step in this cascade,specifically at the insulin receptor kinase activity, which appears tobe diminished (reviewed by Haring, Diabetalogia 1991, 34, 848).

[0009] Protein-tyrosine phosphatases (PTPases) play an important role inthe regulation of phosphorylation of proteins. The interaction ofinsulin with its receptor leads to phosphorylation of certain tyrosinemolecules within the receptor protein, thus activating the receptorkinase. PTPases dephosphorylate the activated insulin receptor,attenuating the tyrosine kinase activity. PTPases can also modulatepost-receptor signaling by catalyzing the dephosphorylation of cellularsubstrates of the insulin receptor kinase. The enzymes that appear mostlikely to closely associate with the insulin receptor and therefore,most likely to regulate the insulin receptor kinase activity, includePTP1B, LAR, PTPα and SH-PTP2 (B. J. Goldstein, J. Cellular Biochemistry1992, 48, 33; B. J. Goldstein, Receptor 1993, 3, 1-15F. Ahmad and B. J.Goldstein Biochim. Biophys Acta 1995, 1248, 57-69).

[0010] McGuire et al. (Diabetes 1991, 40, 939), demonstrated thatnondiabetic glucose intolerant subjects possessed significantly elevatedlevels of PTPase activity in muscle tissue vs. normal subjects, and thatinsulin infusion failed to suppress PTPase activity as it did in insulinsensitive subjects.

[0011] Meyerovitch et al (J. Clinical Invest. 1989, 84, 976) observedsignificantly increased PTPase activity in the livers of two rodentmodels of IDDM, the genetically diabetic BB rat, and the STZ-induceddiabetic rat. Sredy et al (Metabolism, 44, 1074, 1995) observed similarincreased PTPase activity in the livers of obese, diabetic ob/ob mice, agenetic rodent model of NIDDM.

[0012] The compounds of us in the methods of this invention have beenshown to inhibit PTPases derived from rat liver microsomes andhuman-derived recombinant PTPase-1B (hPTP-1B) in vitro. Their synthesisand use in treatments of insulin resistance associated with obesity,glucose intolerance, diabetes mellitus, hypertension and ischemicdiseases of the large and small blood vessels is taught in published PCTApplication WO 99/61435 (Wrobel et al.).

DESCRIPTION OF THE INVENTION

[0013] This invention provides methods of using a pharmacologicalcombination of one or more PTPase inhibiting agents, one or morebiguanide agents, and, optionally one or more sulfonlylurea agents fortreatment of type II diabetes or Syndrome X in a mammal in need of suchtreatment. Also provided are a method of using these agents to treat orinhibit metabolic disorders mediated by insulin resistance orhyperglycemia in a mammal in need thereof. Further included in thisinvention is a method of modulating blood glucose levels in a mammal inneed thereof.

[0014] Each of these methods comprises administering to a mammal in needthereof pharmaceutically effective amounts of:

[0015] a) a PTPase inhibiting agent; and

[0016] b) a biguanide agent; and

[0017] c) optionally, a sulfonylurea agent.

[0018] Biguanide agents useful with this invention include metformin andits pharmaceutically acceptable salt forms. Sulfonylurea agents usefulfor the methods and combinations of this invention may be selected fromthe group of glyburide, glyburide, glipizide, glimepiride,chlorpropamide, tolbutamide, or tolazamide, or a pharmaceuticallyacceptable salt form of these agents.

[0019] PTPase inhibiting agents useful with this invention may beselected as compound of formula I:

[0020] wherein:

[0021] Ar is

[0022] A is hydrogen, halogen, or OH;

[0023] B and D are each, independently, hydrogen, halogen, CN, alkyl of1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms, hydroxyalkyl of1-6 carbon atoms, hydroxyaralkyl of 6-12 carbon atoms, cycloalkyl of 3-8carbon atoms, nitro, amino, —NR¹R^(1a), —NR¹COR^(1a), —NR¹CO₂R^(1a),cycloalkylamino of 3-8 carbon atoms, morpholino, furan-2-yl, furan-3-yl,thiophen-2-yl, thiophen-3-yl, —COR^(1b) or OR;

[0024] R is hydrogen, alkyl of 1-6 carbon atoms, —COR¹, —(CH₂)_(n)CO₂R¹,—CH(R^(1a))CO₂R¹, —SO₂R¹, —(CH₂)_(m)CH(OH)CO₂R¹, —(CH₂)_(m)COCO₂R¹,—(CH₂)_(m)CH═CHCO₂R¹, or —(CH₂)_(m)O(CH₂)_(n)CO₂R¹;

[0025] R¹ is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbonatoms, aryl, or CH₂CO₂R^(1′);

[0026] R^(1′) is hydrogen or alkyl of 1-6 carbon atoms

[0027] E is S, SO, SO₂, O, or NR^(1c);

[0028] X is hydrogen, halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7carbon atoms, CN, aryl, aralkyl of 6-12 carbon atoms, hydroxyalkyl of1-6 carbon atoms, hydroxyaralkyl of 6-12 carbon atoms, perfluoroalkyl of1-6 carbon atoms, alkoxy of 1-6 carbon atoms, aryloxy; arylalkoxy,nitro, amino, NR²R^(2a), NR²COR^(2a), cycloalkylamino of 3-8 carbonatoms, morpholino, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl,pyridylsulfanyl, 2-N,N-dimethylaminoethyl-sulfanyl, —OCH₂CO₂R^(2b) or—COR^(2c);

[0029] Y is hydrogen, halogen, alkyl of 1-6 carbon atoms, aryl, aralkylof 6-12 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxyaralkylof 6-12 carbon atoms, —OR³, SR³, NR³R^(3a), —COR^(3b), morpholine orpiperidine;

[0030] R^(1a), R^(1c), R², R^(2a)R³, R^(3a) are each, independently,hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, oraryl;

[0031] R^(1b) is alkyl of 1-6 carbon atoms or aryl;

[0032] R^(2b) is hydrogen, alkyl of 1-6 carbon atoms;

[0033] R^(2c) and R^(3b) are each, independently, alkyl of 1-6 carbonatoms, aryl, or aralkyl of 6-12 carbon atoms;

[0034] C is hydrogen, halogen or OR⁴;

[0035] R⁴ is hydrogen, alkyl of 1-6 carbon atoms, —CH(R₅)W,—C(CH₃)₂CO₂R⁶, 5-thiazolidine-2,4-dione, —CH(R⁷)(CH₂)_(m)CO₂R⁶, —COR⁶,—PO₃(R⁶)₂, —SO₂R⁶, —(CH₂)_(p)CH(OH)CO₂R⁶, —(CH₂)_(p)COCO₂R⁶,—(CH₂)_(p)CH═CHCO₂R⁶, or —(CH₂)_(p)O(CH₂)_(q)CO₂R⁶;

[0036] R⁵ is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbonatoms, aryl, —CH₂(1H-imidazol-4-yl), —CH₂(3-1H-indolyl),—CH₂CH₂(1,3-dioxo-1,3-dihydro-isoindol-2-yl),—CH₂CH₂(1-oxo-1,3-dihydro-isoindol-2-yl), —CH₂(3-pyridyl), —CH₂CO₂H, or—(CH₂)_(n)G;

[0037] G is NR^(6a)R^(7a), NR⁶COR^(7a),

[0038] W is CO₂R⁶, CONH₂, CONHOH, CN, CONH(CH₂)₂CN, 5-tetrazole,—PO₃(R⁶)₂, —CH₂OH, —CONR^(6b)CHR^(7b), —CH₂NR^(6b)CHR^(7b)CO₂R⁶,—CH₂OCHR^(7b)CO₂R⁶—CH₂Br, or —CONR^(6b)CHR^(7b)CO₂R⁶;

[0039] R⁶, R^(6a), R⁷, R^(7a) are each, independently, is hydrogen,alkyl of 1-6 carbon atoms, or aryl;

[0040] R^(6b) is hydrogen or —COR^(6c);

[0041] R^(6c) is alkyl of 1-6 carbon atoms or aryl;

[0042] R^(7b) is hydrogen, alkyl of 1-6 carbon atoms, or hydroxyalkyl of1-6 carbon atoms;

[0043] Z¹ and Z² are each, independently, hydrogen, halogen, CN, alkylof 1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms, cycloalkyl of3-8 carbon atoms, nitro, amino, —NR¹R^(1a), —NR¹COR^(1a),cycloalkylamino of 3-8 carbon atoms, morpholino, or OR⁸, or Z¹ and Z²may be taken together as a diene unit having the formula—CH═CR⁹—CR¹⁰═CR¹ 1;

[0044] R⁸ is hydrogen, alkyl of 1-6 carbon atoms, or aryl;

[0045] R⁹, R¹⁰, and R¹¹ are each, independently, hydrogen, alkyl of 1-6carbon atoms, aryl, halogen, hydroxy, or alkoxy of 1-6 carbon atoms

[0046] m is 1 to 4

[0047] n is 1 or 2;

[0048] p is 1 to 4;

[0049] q is 1 to 4;

[0050] or a pharmaceutically acceptable salt or ester form thereof.

[0051] The synthesis and PTPase inhibiting and anti-diabetic activitiesof the compounds described herein are demonstrated in published PCTApplication WO 99/61435 (Wrobel et al.), published Dec. 2, 1999, thecontents of which are incorporated herein by reference.

[0052] Pharmaceutically acceptable salts of these compounds can beformed from organic and inorganic acids, for example, acetic, propionic,lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic,malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric,sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic,toluenesulfonic, camphorsulfonic, and similarly known acceptable acidswhen a compound of this invention contains a basic moiety, such as whenR⁵ is CH₂(3-pyridyl), or Y is morpholine or contains similar basicmoieties. Salts may also be formed from organic and inorganic bases,preferably alkali metal salts, for example, sodium, lithium, orpotassium, when a compound of this invention contains a carboxylate orphenolic moiety.

[0053] Alkyl includes both straight chain as well as branched moieties.Halogen means bromine, chlorine, fluorine, and iodine. It is preferredthat the aryl portion of the aryl or aralkyl substituent is a phenyl ornaphthyl; with phenyl being most preferred. The aryl moiety may beoptionally mono-, di-, or tri-substituted with a substituent selectedfrom the group consisting of alkyl of 1-6 carbon atoms, alkoxy of 1-6carbon atoms, trifluoromethyl, halogen, alkoxycarbonyl of 2-7 carbonatoms, alkylamino of 1-6 carbon atoms, and dialkylamino in which each ofthe alkyl groups is of 1-6 carbon atoms, nitro, cyano, —CO₂H,alkylcarbonyloxy of 2-7 carbon atoms, and alkylcarbonyl of 2-7 carbonatoms.

[0054] The PTPase inhibiting compounds used in the methods of thisinvention may contain an asymmetric carbon atom and some of thecompounds of this invention may contain one or more asymmetric centersand may thus give rise to optical isomers and diastereomers. While shownwithout respect to stereochemistry in Formula I, the present inventionincludes such optical isomers and diastereomers; as well as the racemicand resolved, enantiomerically pure R and S stereoisomers; as well asother mixtures of the R and S stereoisomers and pharmaceuticallyacceptable salts thereof.

[0055] The compounds of this invention may be atropisomers by virtue ofpossible restricted or slow rotation about the aryl-tricyclic oraryl-bicyle single bond. This restricted rotation creates additionalchirality and leads to enantiomeric forms. If there is an additionalchiral center in the molecule, diasteriomers exist and can be seen inthe NMR and via other analytical techniques. While shown without respectto atropisomer stereochemistry in Formula I, the present inventionincludes such atoropisomers (enantiomers and diastereomers; as well asthe racemic, resolved, pure diastereomers and mixutures of diasteomers)and pharmaceutically acceptable salts thereof.

[0056] Preferred PTPase inhibiting compounds of use in this inventioninclude those having the structure:

[0057] wherein:

[0058] A is hydrogen or halogen;

[0059] B and D are each, independently, hydrogen, halogen, CN, alkyl of1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms, branched alkyl,cycloalkyl of 3-8 carbon atoms, nitro or OR;

[0060] R is hydrogen or alkyl of 1-6 carbon atoms;

[0061] E is S, or O;

[0062] X is hydrogen, halogen, alkyl of 1-6 carbon atoms, CN,perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, aryloxy;arylalkoxy, nitro, amino, NR²R^(2a), NR²COR^(2a), cycloalkylamino,morpholino, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl,pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl;

[0063] R¹, R^(1a), R², R^(2a), R³, and R^(3a) are each, independently,hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, oraryl;

[0064] Y is hydrogen, halogen, OR³, SR³, NR³R^(3a) or morpholine;

[0065] C is hydrogen, halogen, or OR⁴;

[0066] R⁴ is hydrogen, alkyl of 1-6 carbon atoms, —CH(R⁵)W,—C(CH₃)₂CO₂R⁶, 5-thiazolidine-2,4-dione, —CH(R⁷)(CH₂)_(m)CO₂R⁶, —COR⁶,—PO₃(R⁶)₂, —SO₂R⁶, —(CH₂)_(p)CH(OH)CO₂R⁶, —(CH₂)_(p)COCO₂R⁶,—(CH₂)_(p)CH═CHCO₂R⁶, or —(CH₂)_(p)O(CH₂)_(q)CO₂R⁶;

[0067] R⁵ is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbonatoms, aryl, —CH₂(1H-imidazol-4-yl), —CH₂(3-1H-indolyl),—CH₂CH₂(1,3-dioxo-1,3-dihydro-isoindol-2-yl),—CH₂CH₂(1-oxo-1,3-dihydro-isoindol-2-yl), or —CH₂(3-pyridyl);

[0068] W is CO₂R⁶, —CONH₂, —CONHOH, or 5-tetrazole, or—CONR^(6b)CHR^(7b)CO₂R⁶; R⁶, R^(6a), R^(6b), R⁷, R^(7a), and R^(7b) areeach, independently, hydrogen, alkyl of 1-6 carbon atoms, or aryl;

[0069] Z¹ and Z² are each, independently, hydrogen, halogen, CN, alkylof 1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms, cycloalkyl of3-8 carbon atoms, nitro, amino, —NR¹R^(1a), —NR¹COR^(1a),cycloalkylamino of 3-8 carbon atoms, morpholino, or OR⁸, or Z¹ and Z²may be taken together as a diene unit having the formula—CH═CR⁹—CR¹⁰═CH—;

[0070] R⁹ and R¹⁰ are independently, hydrogen, or alkyl of 1-6 carbonatoms;

[0071] p is 1 to 4;

[0072] q is 1 to 4;

[0073] or a pharmaceutically acceptable salt or ester form thereof.

[0074] More preferred PTPase inhibiting compounds for use in the methodsof this invention include those of the structure:

[0075] wherein:

[0076] A is hydrogen;

[0077] B and D are each, independently, halogen, alkyl of 1-6 carbonatoms, aryl, aralkyl of 6-12 carbon atoms, or cycloalkyl of 3-8 carbonatoms;

[0078] E is S or O;

[0079] X is hydrogen, halogen, alkyl of 1-6 carbon atoms, perfluoroalkylof 1-6 carbon atoms, CN, alkoxy of 1-6 carbon atoms, aryloxy, arylalkoxyof 6-12 carbon atoms, arylsulfanyl;

[0080] Y is hydrogen or —NR¹R², or morpholine;

[0081] R¹ and R² are each, independently, hydrogen or alkyl of 1-6carbon atoms, aralkyl of 6-12 carbon atoms, or aryl;

[0082] C is OR⁴;

[0083] R⁴ is hydrogen, alkyl of 1-6 carbon atoms, —CH(R⁵)W, or5-thiazolidine-2,4-dione;

[0084] R⁵ is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbonatoms, aryl, —CH₂(3-1H-indolyl),—CH₂CH₂(1,3-dioxo-1,3-dihydro-isoindol-2-yl), or—CH₂CH₂(1-oxo-1,3-dihydro-isoindol-2-yl);

[0085] W is —CO₂R⁶, —CONH₂, —CONHOH, 5-tetrazole, —PO₃(R⁶)₂, or—CONR⁶CHR⁶CO₂R⁶

[0086] R⁶ is hydrogen or alkyl of 1-6 carbon atoms;

[0087] Z¹ and Z² are taken together as a diene unit having the formula—CH═CH—H═CH—;

[0088] or a pharmaceutically acceptable salt thereof.

[0089] Even more preferred PTPase inhibiting compounds of this inventioninclude:

[0090](R)-2-[2,6-dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-3-phenyl-propionicacid;

[0091](R)-2-[2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-ethyl-phenoxy]-3-phenyl-propionicacid;

[0092](R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionicacid;

[0093](R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-fluoro-phenoxy]-3-phenyl-propionicacid;

[0094][4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phenoxy]-aceticacid;

[0095](R)-2-[2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-sec-butyl-phenoxy]-3-phenyl-propionicacid;

[0096](R)-2-[2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-isopropyl-phenoxy]-3-phenyl-propionicacid;

[0097](R)-2-[2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenoxy]-3-phenyl-propionicacid

[0098](R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-isopropyl-phenoxy]-3-phenyl-propionicacid;

[0099](R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenoxy]-3-phenyl-propionicacid;

[0100](R)-2-[2,6-dibromo-4-(2,3-dimethyl-9-phenylsulfanyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-3-phenyl-propionicacid;

[0101](R)-2-[2,6-dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-4-phenyl-butyricacid;

[0102](S)-2-[2,6-dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-4-phenyl-butyricacid;

[0103]2-[2,6-dibromo-4-(9-bromo-3-methyl-2-morpholin-4-ylmethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-3-phenyl-propionicacid;

[0104](R)-2-[2,6-dibromo-4-(2,3-dimethyl-9-phenylsulfanyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-propionicacid;

[0105][2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-nitro-phenoxy]-3-phenyl-propionicacid;

[0106] 2,6-dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol;

[0107]2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-nitro-phenol;

[0108](R)-2-[2,6-dibromo-4-(9-bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]-thiophen-4-yl)-phenoxy]-3-phenyl-propionicacid;

[0109](R)-2-[2,6-dibromo-4-(2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-phenoxy]-3-phenyl-propionicacid,

[0110](2R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phenoxy]-3-phenyl-propionicacid,

[0111](R)-2-[4-(9-bromo-2-3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionicacid,

[0112]{(2R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionylamino}-aceticacid;

[0113]{(2R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionylamino}-aceticacid

[0114] or pharmaceutically acceptable salts thereof.

[0115] Among the most preferred PTPase inhibiting compounds for use inthe present inventions is(2R)-2-[4-(9-Bromo-2,3-dimethyl-naptho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionicacid, having the structure:

[0116] or its pharmaceutically acceptable salt or ester forms.

[0117] Metformin hydrochloride useful in the methods and combinations iscommercially available in 500 mg, 850 mg and 1000 mg tablets under theGLUCOPHAGE® tradename from Bristol Meyers Squibb. Metforminhydrochloride may be administered in humans at an initial daily dose offrom 500 mg to about 800 mg and increased, as needed, to a maximum dailydosage of 2550 mg.

[0118] Among the more preferred sulfonylurea agents of this inventionare the non-limiting group of glyburide, glyburide, glipizide,glimepiride, chlorpropamide, tolbutamide, or tolazamide, or apharmaceutically acceptable salt form of these agents. Each of theseagents may be produced by methods known in the art. These agents mayalso be administered at the pharmaceutically or therapeuticallyeffective dosages or amounts known in the art for these compounds, suchas those described in the Physician's Desk Reference 2001, 55 Edition,Copyright 2001, published by Medical Economics Company, Inc., therelevant portions describing each of these products being incorporatedherein by reference.

[0119] Glyburide is commercially available in the form of 1.25 mg, 2.5mg and 5 mg DIABETA® brand tablets from Aventis Pharmaceuticals.Glyburide may be administered at an initial daily dose of from 1.25 mgto 5 mg and raised incrementally, as needed, to a maximum daily dose ofup to about 20 mg.

[0120] Glipizide is commercially available in the form of 5 mg and 10 mgGLUCOTROL® tablets and 2 mg, 5 mg and 10 mg GLUCOTROL XL® extendedrelease tablets from Pfizer Inc. 5 mg and 10 mg forms of glipizide arealso available commercially from Geneva Pharmaceuticals Inc, MylanPharmaceuticals Inc. and Watson Laboratories Inc. Glipizide may beadministered at an initial dose of from about 2.5 mg to about 5 mg perday, generally given prior to breakfast. The dosage may be increasedincrementally, as needed, to a maximum dosage of about 15 mg per day.

[0121] Glimepiride is available in 1 2 and 4 mg AMARYL® brand tabletsfrom Aventis Pharmaceuticals. Glimepiride may be administered at aninitial single daily dose of from about 1 to 2 mg and increased asneeded to a maximum daily dose of about 8 mg, with a usual maintenancedose being between about 1 and 4 mg.

[0122] Chlorpropamide is commercially available in the form of 100 mgand 500 mg DIABINESE® tablets from Pfizer Inc. and in 100 mg and 250 mgtablets from Mylan Pharmaceuticals Inc. Chlorpropamide may beadministered at an initial daily dose of between about 100 mg and about250 mg, and increase as need to a daily maintenance dose of betweenabout 250 mg and 500 mg.

[0123] Tolbutamide is available in 500 mg tablets from MylanPharmaceuticals Inc and may be administered at an initial daily dose offrom 1,000 to 2,000 mg per day to start, in 2 divided doses. It may beincreased to a maximum dosage of about 3,000 mg (3 g) a day.

[0124] Tolazamide is available in 250 mg and 500 mg tablets from MylanPharmaceuticals Inc and may be administered at an initial daily dose offrom 100 to 250 mg once a day and may be increased to about 1,000 mg perday.

[0125] A combination of glyburide and metformin hydrochloride useful inthe methods and combinations is also commercially available in 1.25mg/250 mg, respectively, 2.5 mg/500 mg and 2.5 mg/500 mg tablets underthe GLUCOVANCE® tradename from Bristol Meyers Squibb.

[0126] This invention provides methods for treating, preventing,inhibiting or ameliorating the basis or symptoms of type II diabetes ina mammal, preferably in a human, in need of such help. This inventionalso comprises a method of treating, inhibiting, preventing or reducingthe symptoms, physiological basis or causative elements of metabolicdisorders mediated by insulin resistance or hyperglycemia in a mammal inneed thereof, particularly including those typically associated withobesity or glucose intolerance. Also provided by this invention is amethod for modulating blood glucose levels in a mammal in need thereof.Modulating blood glucose levels as used herein is understood to indicatemaintaining glucose levels within clinically normal ranges or loweringelevated blood glucose levels to a more clinically desirable level orrange.

[0127] The methods herein each comprise administering to a mammal inneed thereof a pharmaceutically or therapeutically effective amount of aPTPase inhibitor of this invention, as described herein, a biguanideagent and, optionally, a pharmaceutically or therapeutically effectiveamount of a sulfonylurea agent. As used herein a pharmaceutically ortherapeutically effective amount is understood to be at least a minimalamount which provides a medical improvement in the symptoms of thespecific malady or disorder experienced by the mammal in question.Preferably, the recipient will experience a reduction, inhibition orremoval of the biological basis for the malady in question.

[0128] This invention also comprises methods for treatment, inhibitionor prophylaxis of Syndrome X and its related and encompassed maladies ina mammal in need thererof. These methods include the treatment ofhyperglycemia, hypertension, cardiovascular and cerebrovascular disease,including atherosclerosis, and renal disease associated with Syndrome X.Also included in these methods are the treatment, inhibition orprophylaxis in a mammal currently experiencing or subject to symptoms orconditions of Syndrome X are those for diabetic neuropathy,microalbuminaria, albuminaria, glomerular sclerosis, glomerulonephritis,nephrotic syndrome, end stage renal disease and hypertensivenephrosclerosis. This invention also includes methods for improving thecardiovascular and cerebrovascular risk profiles in a mammal in a mammalexperiencing or subject to Syndrome X. Such an improvement incardiovascular or cerebrovascular risk profile may also be characterizedas a decrease in the risk of adverse cardiovascular or cerebrovascularevents associated with the conditions described herein, includingatherosclerosis, hyperlipidemia, hypertension, etc. As described herein,each of these methods comprises administering to a mammal in need ofsuch treatment a pharmaceutically effective amount of a PTPase inhibitorof this invention, or a pharmaceutically acceptable salt form thereof, apharmaceutically effective amount of a biguanide agent and, optionally,a pharmaceutically effective amount of a sulfonylurea agent.

[0129] Another aspect of this invention is a pharmaceutical compositioncomprising a pharmaceutically amount of a PTPase inhibiting compound ofthis invention, a pharmaceutically effective amount of a biguanide agentand, optionally, a pharmaceutically effective amount of a sulfonylureaagent, and one or more pharmaceutically acceptable carriers orexcipients.

[0130] Effective administration of the PTPase inhibiting compounds ofthis invention may be given at a daily dosage of from about 1 mg/kg toabout 250 mg/kg, and may given in a single dose or in two or moredivided doses. Such doses may be administered in any manner useful indirecting the active compounds herein to the recipient's bloodstream,including orally, via implants, parenterally (including intravenous,intraperitoneal and subcutaneous injections), rectally, vaginally, andtransdermally. For the purposes of this disclosure, transdermaladministrations are understood to include all administrations across thesurface of the body and the inner linings of bodily passages includingepithelial and mucosal tissues. Such administrations may be carried outusing the present compounds, or pharmaceutically acceptable saltsthereof, in lotions, creams, foams, patches, suspensions, solutions, andsuppositories (rectal and vaginal).

[0131] Oral formulations containing the active compounds of thisinvention may comprise any conventionally used oral forms, includingtablets, capsules, buccal forms, troches, lozenges and oral liquids,suspensions or solutions. Capsules may contain mixtures of the activecompound(s) with inert fillers and/or diluents such as thepharmaceutically acceptable starches (e.g. corn, potato or tapiocastarch), sugars, artificial sweetening agents, powdered celluloses, suchas crystalline and microcrystalline celluloses, flours, gelatins, gums,etc. Useful tablet formulations may be made by conventional compression,wet granulation or dry granulation methods and utilize pharmaceuticallyacceptable diluents, binding agents, lubricants, disintegrants,suspending or stabilizing agents, including, but not limited to,magnesium stearate, stearic acid, talc, sodium lauryl sulfate,microcrystalline cellulose, carboxymethylcellulose calcium,polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, xanthan gum,sodium citrate, complex silicates, calcium carbonate, glycine, dextrin,sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose,kaolin, mannitol, sodium chloride, talc, dry starches and powderedsugar. Oral formulations herein may utilize standard delay or timerelease formulations to alter the absorption of the active compound(s).Suppository formulations may be made from traditional materials,including cocoa butter, with or without the addition of waxes to alterthe suppository's melting point, and glycerin. Water soluble suppositorybases, such as polyethylene glycols of various molecular weights, mayalso be used.

[0132] It is understood that the dosage, regimen and mode ofadministration of these compounds will vary according to the malady andthe individual being treated and will be subject to the judgment of themedical practitioner involved. It is preferred that the administrationof one or more of the compounds herein begin at a low dose and beincreased until the desired effects are achieved. It is also preferredthat the recipient also utilize art recognized lifestyle patterns forreducing the incidence of the maladies described herein. These includemaintenance of an appropriate diet and exercise regimen, as recommendedby a medical practitioner familiar with the physical condition of therecipient.

[0133] The following are representative PTPase inhibiting compoundexamples useful in the methods of this invention. Their synthesis isdescribed in published PCT Application WO 99/61435, published Dec. 2,1999, the contents of which are incorporated herein by reference.

EXAMPLE 1

[0134] 2,3-Dimethyl-thiophene;

EXAMPLE 2

[0135] 4,5-Dimethylthiophene-2-yl-(phenyl)-methanol;

EXAMPLE 3

[0136] 2-Benzyl-4,5 dimethylthiophene;

EXAMPLE 4

[0137](2-Benzyl-4,5-dimethyl-thiophen-3-yl)-(4-methoxy-phenyl)-methanone;

EXAMPLE 5

[0138] 4-(2,3-Dimethyl-naphtho[2,3-b]thiophen-4-yl-phenol;

EXAMPLE 6

[0139] Acetic Acid 4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenylester;

EXAMPLE 7

[0140] Acetic Acid4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenyl ester;

EXAMPLE 8

[0141] 4-(9-BROMO-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol;

EXAMPLE 9

[0142]2,6-Dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol;

EXAMPLE 10

[0143] Methanesulfonic acid4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenyl ester;

EXAMPLE 11

[0144] Methanesulfonic acid4-(9-iodo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenyl ester;

EXAMPLE 12

[0145]4-(2,3-Dimethyl-9-phenylsulfanyl-naphtho[2,3-b]thiophen-4-yl)-phenol;

EXAMPLE 13

[0146]2,6-Dibromo-4-(2,3-dimethyl-9-phenylsulfanyl-naphtho[2,3-b]thiophen-4-yl)-phenol;

EXAMPLE 14

[0147] Acetic acid4-(9-bromo-2-chloromethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-phenylester;

EXAMPLE 15

[0148]4-(9-Bromo-3-methyl-2-morpholin-4-yl)methyl-naphtho[2,3-b]thiophen-4-yl)-phenol;

EXAMPLE 16

[0149]4-(9-Bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-acetate;

EXAMPLE 17

[0150]4-(9-Bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-phenol;

EXAMPLE 18

[0151]2,6-Dibromo-4-(9-bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-phenol;

EXAMPLE 19

[0152]2,6-Dibromo-4-(9-bromo-3-methyl-2-morpholin-4-ylmethyl-naphtho[2,3-b]thiophen-4-yl)-phenol;

EXAMPLE 20

[0153]4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-nitro-phenol;

EXAMPLE 21

[0154]2-Bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-nitro-phenol;

EXAMPLE 22

[0155]2-Amino-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol;

EXAMPLE 23

[0156]2-Amino-6-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol;

EXAMPLE 24

[0157][2-Bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-nitro-phenoxy]-aceticacid;

EXAMPLE 25

[0158] (S)-2-Hydroxy-3-phenylpropionic acid, methyl ester;

EXAMPLE 26

[0159] (S)-2-[4-Nitrobenzoyl-]-4-phenylbutyric acid, ethyl ester;

EXAMPLE 27

[0160] (S)-2-Hydroxy-4-phenylbutyric Acid, ethyl ester;

EXAMPLE 28

[0161](R)-2-[2,6-Dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]3-phenyl-propionicacid methyl ester;

EXAMPLE 29

[0162](R)-2-[2,6-Dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]3-phenyl-propionicacid;

EXAMPLE 30

[0163](R)-2-[2,6-Dibromo-4-(9-bromo-2,3-dimethylnaptho[2,3-b]thien-4-yl)-phenoxy]-propanoicacid;

EXAMPLE 31

[0164](S)-2-[2,6-Dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-4-phenyl-butyricacid;

EXAMPLE 32

[0165](R)-2-[2,6-Dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-4-phenyl-butyricacid;

EXAMPLE 33

[0166](R)-2-[2,6-dibromo-4-(2,3-dimethyl-9-phenylsulfanyl-naphtho[2,3-b]-thiophen-4-yl)-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 34

[0167](R)-2-[2,6-Dibromo-4-(2,3-dimethyl-9-phenylsulfanyl-naphtho[2,3-b]-thiophen-4-yl)-phenoxy]-propionicacid;

EXAMPLE 35

[0168]2-[2,6-Dibromo-4-(9-bromo-3-methyl-2-morpholin-4-ylmethyl-naphtho-[2,3-b]thiophen-4-yl)-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 36

[0169]2-[^(2,6)-Dibromo-4-(9-bromo-3-methyl-2-morpholin-4-ylmethyl-naphtho-[2,3-b]thiophen-4-yl)-phenoxy]-propionicacid;

EXAMPLE 37

[0170](R)-2-[2,6-Dibromo-4-(9-bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 38

[0171][2-Bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-nitro-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 39

[0172]2-Bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-isopropyl-phenol;

EXAMPLE 40

[0173](R)-2-[2-Bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-isopropyl-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 41

[0174](R)-2-[4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-isopropyl-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 42

[0175](R)-2-[2-Bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-sec-butyl-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 43

[0176](R)-2-[2-Bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-ethyl-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 44

[0177](R)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-isopropyl-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 45

[0178](R)-2-[2-Cyclopentyl-4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 46

[0179](R)-2-[4-(2,3-Dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 47

[0180]R)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenoxy]-3-phenyl-propionicacid;

EXAMPLE48-(R)-2-[2-Bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenoxy]-3-phenyl-propionicacid; EXAMPLE 49

[0181](R)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 50

[0182](R)-2-[4-(2,3-Dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 51

[0183](R)-2-[4-(2,3-Dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-fluoro-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 52

[0184](R)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-fluoro-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 53

[0185][4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phenoxy]-aceticacid;

EXAMPLE 54

[0186](2R)-2-[2,6-Dibromo-4-(2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 55

[0187](2R)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 56

[0188][3-Bromo-5-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-hydroxy-phenyl]-carbamicacid tert-butyl ester;

EXAMPLE 57

[0189]9-Bromo-4-(3-bromo-methoxy-5-nitro-phenyl)-2,3-dimethyl-naphtho[2,3-b]thiophene;

EXAMPLE 58

[0190]3-Bromo-5-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-methoxy-phenylamine;

EXAMPLE 59

[0191][3-Bromo-5-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-methoxy-phenylamino]-aceticacid methyl ester;

EXAMPLE 60

[0192][3-Bromo-5-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-methoxy-phenylamino]-aceticacid;

EXAMPLE 61

[0193](R)-2-[4-(9-Bromo-2-,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 62

[0194]{(2R)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionylamino}-aceticacid;

EXAMPLE 63

[0195]{(2R)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionylamino}-aceticacid;

EXAMPLE 64

[0196](2R)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 65

[0197](2S)-2-[4-(9-Bromo-2-,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 66

[0198](2R)-2-[4-(9-Bromo-2,3-dimethyl-1-oxo-1H-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 67

[0199](R)-2-[4-(2-,3-Dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 68

[0200]{(2R)-2-[4-(2,3-Dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionylamino}-aceticacid;

EXAMPLE 69

[0201] 4-(2,3-Dimethyl-naphtho[2,3-b]furan-4-yl)-2,6-diethyl-phenol;

EXAMPLE 70

[0202](R)-2-[4-(9-Bromo-2-,3-dimethyl-naphtho[2,3-b]furan-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 71

[0203](R)-2-[2-Cyclopentyl-4-(2-,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-propionicacid;

EXAMPLE 72

[0204](R)-2-[4-(9-Bromo-2-,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenoxy]-propionicacid;

EXAMPLE 73

[0205]4-[4-(9-Bromo-2-,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenoxy]-butyricacid;

EXAMPLE 74

[0206] 2-Cyclopentyl-4-(2-,3-dimethyl-naphtho[2,3-b]furan-4-yl)-phenol;

EXAMPLE 75 Acetic acid2-cyclopentyl-4-(2-,3-dimethyl-naphtho[2,3-b]furan-4-yl)-phenyl ester;EXAMPLE 76

[0207](R)-2-[4-(2-,3-Dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-ethyl-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 77

[0208](R)-2-[4-(9-Bromo-2-,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-ethyl-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 78

[0209]2-Bromo-4-(2-,3-dimethyl-naphtho[2,3-b]furan-4-yl)-6-ethyl-phenol;

EXAMPLE 79

[0210](R)-2-[2-Bromo-4-(2-,3-dimethyl-naphtho[2,3-b]furan-4-yl)-6-ethyl-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 80

[0211]4-[2-Bromo-4-(2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-6-ethyl-phenoxy]-butyricacid;

EXAMPLE 81

[0212]4-[2-Bromo-4-(2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-6-ethyl-phenoxy]-butyramide0.4 hydrate;

EXAMPLE 82

[0213] 4-(2,3-Dimethyl-naphtho[2,3-b]furan-4-yl)-2-ethyl-phenol;

EXAMPLE 83

[0214](R)-2-[4-(9-Bromo-2-,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-propyl-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 84

[0215][9-Bromo-4-(4-methoxy-3,5-dimethylphenyl)-3-methylnaphtho[2,3-b]-thien-2-yl]methylacetate;

EXAMPLE 85

[0216]4-(9-Bromo-2-,3-dimethyl-naphtho[2,3-b]thien-4-yl)-2-methyl-phenylacetate;

EXAMPLE 86 Acetic acid4-(9-bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]-thiophen-4-yl)-2,6-dimethyl-phenylester; EXAMPLE 87

[0217]2-[4-(9-Bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionicacid; and

EXAMPLE 88

[0218](2R)-2-[4-(9-Bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]-thiophen-4-yl)-2,6-diisopropyl-phenoxy]-3-phenyl-propionicacid;

[0219] or the pharmaceutically acceptable salt or ester forms thereof.

What is claimed:
 1. A method for treatment of Syndrome X or type IIdiabetes in a mammal, the method comprising administering to a mammal inneed thereof: a) a pharmaceutically effective amount of a biguanideagent; and b) a pharmaceutically effective amount of a PTPase inhibitingcompound of formula I:

wherein Ar is

A is hydrogen, halogen, or OH; B and D are each, independently,hydrogen, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxyaralkyl of 6-12carbon atoms, cycloalkyl of 3-8 carbon atoms, nitro, amino, —NR¹R^(1a),—NR¹COR^(1a), —NR¹CO₂R^(1a), cycloalkylamino of 3-8 carbon atoms,morpholino, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl,—COR^(1b) or OR; R is hydrogen, alkyl of 1-6 carbon atoms, —COR¹,—(CH₂)_(n)CO₂R¹, —CH(R^(1a))CO₂R¹, —SO₂R¹, —(CH₂)_(m)CH(OH)CO₂R¹,—(CH₂)_(m)COCO₂R¹, —(CH₂)_(m)CH═CHCO₂R¹, or —(CH₂)_(m)O(CH₂)_(o)CO₂R¹;R¹ is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms,aryl, or CH₂CO₂R^(1′); R^(1′) is hydrogen or alkyl of 1-6 carbon atoms Eis S, SO, SO₂, O, or NR^(1c); X is hydrogen, halogen, alkyl of 1-6carbon atoms, alkenyl of 2-7 carbon atoms, CN, aryl, aralkyl of 6-12carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxyaralkyl of 6-12carbon atoms, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbonatoms, aryloxy; arylalkoxy, nitro, amino, NR²R^(2a), NR²COR^(2a),cycloalkylamino of 3-8 carbon atoms, morpholino, alkylsulfanyl of 1-6carbon atoms, arylsulfanyl, pyridylsulfanyl,2-N,N-dimethylaminoethyl-sulfanyl, —OCH₂CO₂R^(2b) or —COR^(2c); Y ishydrogen, halogen, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxyaralkyl of 6-12carbon atoms, —OR³, SR³, NR³R^(3a), —COR^(3b), morpholine or piperidine;R^(1a), R^(1c), R², R^(2a)R³, R^(3a) are each, independently, hydrogen,alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, or aryl; R^(1b)is alkyl of 1-6 carbon atoms or aryl; R^(2b) is hydrogen, alkyl of 1-6carbon atoms; R^(2c) and R^(3b) are each, independently, alkyl of 1-6carbon atoms, aryl, or aralkyl of 6-12 carbon atoms; C is hydrogen,halogen or OR⁴; R⁴ is hydrogen, alkyl of 1-6 carbon atoms, —CH(R₅)W,—C(CH₃)₂CO₂R⁶, 5-thiazolidine-2,4-dione, —CH(R⁷)(CH₂)_(m)CO₂R⁶, —COR⁶,—PO₃(R⁶)₂, —SO₂R⁶, —(CH₂)_(p)CH(OH)CO₂R⁶, —(CH₂)_(p)COCO₂R⁶,—(CH₂)_(p)CH═CHCO₂R⁶, or —(CH₂)_(p)O(CH₂)_(q)CO₂R⁶; R⁵ is hydrogen,alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, aryl,—CH₂(1H-imidazol-4-yl), —CH₂(3-1H-indolyl),—CH₂CH₂(1,3-dioxo-1,3-dihydro-isoindol-2-yl),—CH₂CH₂(1-oxo-1,3-dihydro-isoindol-2-yl), —CH₂(3-pyridyl), —CH₂CO₂H, or—(CH₂)_(n)G; G is NR^(6a)R^(7a), NR^(6a)COR^(7a),

W is CO₂R⁶, CONH₂, CONHOH, CN, CONH(CH₂)₂CN, 5-tetrazole, —PO₃(R⁶)₂,—CH₂OH, —CONR^(6b)CHR^(7b), —CH₂NR^(6b)CHR^(7b)CO₂R⁶,—CH₂OCHR^(7b)CO₂R⁶—CH₂Br, or —CONR^(6b)CHR^(7b)CO₂R⁶; R⁶, R^(6a), R⁷,R^(7a) are each, independently, is hydrogen, alkyl of 1-6 carbon atoms,or aryl; R^(6b) is hydrogen or —COR^(6c); R^(6c) is alkyl of 1-6 carbonatoms or aryl; R^(7b) is hydrogen, alkyl of 1-6 carbon atoms, orhydroxyalkyl of 1-6 carbon atoms; Z¹ and Z² are each, independently,hydrogen, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12carbon atoms, cycloalkyl of 3-8 carbon atoms, nitro, amino, —NR¹R^(1a),—NR¹COR^(1a), cycloalkylamino of 3-8 carbon atoms, morpholino, or OR⁸,or Z¹ and Z² may be taken together as a diene unit having the formula—CH═CR⁹—CR¹⁰═CR¹¹—; R⁸ is hydrogen, alkyl of 1-6 carbon atoms, or aryl;R⁹, R¹⁰, and R¹¹ are each, independently, hydrogen, alkyl of 1-6 carbonatoms, aryl, halogen, hydroxy, or alkoxy of 1-6 carbon atoms m is 1 to 4n is 1 or 2; p is 1 to 4; q is 1 to 4; or a pharmaceutically acceptablesalt thereof; and c) optionally, a pharmaceutically effective amount ofa sulfonylurea agent, or a pharmaceutically acceptable salt formthereof.
 2. The method of claim 1 wherein the PTPase inhibiting compoundis as defined in claim 1, wherein: Ar is B

A is hydrogen or halogen B and D are each, independently, hydrogen,halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12 carbonatoms, branched alkyl, cycloalkyl of 3-8 carbon atoms, nitro or OR; R ishydrogen or alkyl of 1-6 carbon atoms; E is S, or O; X is hydrogen,halogen, alkyl of 1-6 carbon atoms, CN, perfluoroalkyl of 1-6 carbonatoms, alkoxy of 1-6 carbon atoms, aryloxy; arylalkoxy, nitro, amino,NR²R^(2a), NR²COR^(2a), cycloalkylamino, morpholino, alkylsulfanyl of1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, or2-N,N-dimethylaminoethylsulfanyl; R¹, R^(1a), R², R^(2a), R³, and R^(3a)are each, independently, hydrogen, alkyl of 1-6 carbon atoms, aralkyl of6-12 carbon atoms, or aryl; Y is hydrogen, halogen, OR³, SR³, NR³R^(3a),or morpholine; C is hydrogen, halogen, or OR⁴; R⁴ is hydrogen, alkyl of1-6 carbon atoms, —CH(R⁵)W, —C(CH₃)₂CO₂R⁶, 5-thiazolidine-2,4-dione,—CH(R⁷)(CH₂)_(m)CO₂R⁶, —COR⁶, —PO₃(R⁶)₂, —SO₂R⁶, —(CH₂)_(p)CH(OH)CO₂R⁶,—(CH₂)_(p)COCO₂R⁶, —(CH₂)_(p)CH═CHCO₂R⁶, —(CH₂)_(p)O(CH₂)_(q)CO₂R⁶; R⁵is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms,aryl, —CH₂(1H-imidazol-4-yl), —CH₂(3-1H-indolyl),—CH₂CH₂(1,3-dioxo-1,3-dihydro-isoindol-2-yl),—CH₂CH₂(1-oxo-1,3-dihydro-isoindol-2-yl), or —CH₂(3-pyridyl); W isCO₂R⁶, —CONH₂, —CONHOH, 5-tetrazole, or —CONR^(6b)CHR^(7b)CO₂R⁶; R⁶,R^(6a), R^(6b), R⁷, R^(7a), and R^(7b) are each, independently,hydrogen, alkyl of 1-6 carbon atoms, or aryl; Z¹ and Z² are each,independently, hydrogen, halogen, CN, alkyl of 1-6 carbon atoms, aryl,aralkyl of 6-12 carbon atoms, cycloalkyl of 3-8 carbon atoms, nitro,amino, —NR¹R^(1a), —NR¹COR^(1a), cycloalkylamino of 3-8 carbon atoms,morpholino, or OR⁸, or Z¹ and Z² may be taken together as a diene unithaving the formula —CH═CR⁹—CR¹⁰═CH—; R⁹ and R¹⁰ are each, independently,hydrogen, or alkyl of 1-6 carbon atoms; p is 1 to 4; q is 1 to 4; or apharmaceutically acceptable salt thereof.
 3. The method of claim 2wherein the PTPase inhibiting compound is defined in claim 2, wherein Ais hydrogen; B and D are each, independently, halogen, alkyl of 1-6carbon atoms, aryl, aralkyl of 6-12 carbon atoms, or cycloalkyl of 3-8carbon atoms; E is S or O; X is hydrogen, halogen, alkyl of 1-6 carbonatoms, perfluoroalkyl of 1-6 carbon atoms, CN, alkoxy of 1-6 carbonatoms, aryloxy, arylalkoxy of 6-12 carbon atoms, arylsulfanyl; Y ishydrogen, —NR¹R², or morpholine; R¹ and R² are each, independently,hydrogen or alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, oraryl; C is OR⁴; R⁴ is hydrogen, alkyl of 1-6 carbon atoms, —CH(R⁵)W, or5-thiazolidine-2,4-dione; R⁵ is hydrogen, alkyl of 1-6 carbon atoms,aralkyl of 6-12 carbon atoms, aryl, —CH₂(3-1H-indolyl),—CH₂CH₂(1,3-dioxo-1,3-dihydro-isoindol-2-yl), or—CH₂CH₂(1-oxo-1,3-dihydro-isoindol-2-yl); W is —CO₂R⁶, —CONH₂, —CONHOH,5-tetrazole, —PO₃(R⁶)₂, or —CONR⁶CHR⁶CO₂R⁶; R⁶ is hydrogen or alkyl of1-6 carbon atoms; Z¹ and Z² are taken together as a diene unit havingthe formula —CH═CH—H═CH—; or a pharmaceutically acceptable salt thereof.4. The method of claim 1 wherein the PTPase inhibiting compound is(2R)-2-[4-(9-Bromo-2,3-dimethyl-naptho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionicacid, or a pharmaceutically acceptable salt form thereof.
 5. The methodof claim 1 wherein the PTPase inhibiting compound is selected from thegroup of:(R)-2-[2,6-dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-3-phenyl-propionicacid;(R)-2-[2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-ethyl-phenoxy]-3-phenyl-propionicacid;(R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionicacid;(R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-fluoro-phenoxy]-3-phenyl-propionicacid;[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phenoxy]-aceticacid; or a pharmaceutically acceptable salt form thereof.
 6. The methodof claim 1 wherein the PTPase inhibiting compound is selected from thegroup of:(R)-2-[2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-sec-butyl-phenoxy]-3-phenyl-propionicacid;(R)-2-[2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-isopropyl-phenoxy]-3-phenyl-propionicacid;(R)-2-[2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenoxy]-3-phenyl-propionicacid;(R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-isopropyl-phenoxy]-3-phenyl-propionicacid;(R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenoxy]-3-phenyl-propionicacid; or a pharmaceutically acceptable salt thereof.
 7. The method ofclaim 1 wherein the PTPase inhibiting compound is selected from thegroup of:(R)-2-[2,6-dibromo-4-(2,3-dimethyl-9-phenylsulfanyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-3-phenyl-propionicacid;(R)-2-[2,6-dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-4-phenyl-butyricacid;(S)-2-[2,6-dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-4-phenyl-butyricacid;2-[2,6-dibromo-4-(9-bromo-3-methyl-2-morpholin-4-ylmethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-3-phenyl-propionicacid;(R)-2-[2,6-dibromo-4-(2,3-dimethyl-9-phenylsulfanyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-propionicacid; or a pharmaceutically acceptable salt thereof.
 8. The method ofclaim 1 wherein the PTPase inhibiting compound is selected from thegroup of:[2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-nitro-phenoxy]-3-phenyl-propionicacid;2,6-dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol;2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-nitro-phenol;(R)-2-[2,6-dibromo-4-(9-bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-3-phenyl-propionicacid;(R)-2-[2,6-dibromo-4-(2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-phenoxy]-3-phenyl-propionicacid; or a pharmaceutically acceptable salt thereof.
 9. The method ofclaim 1 wherein the PTPase inhibiting compound is selected from thegroup of:(2R)-2-[4-9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phenoxy]-3-phenyl-propionicacid,(R)-2-[4-(9-bromo-2-,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionicacid;{(2R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionylamino}-aceticacid;{(2R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionylamino}-aceticacid;(2R)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-3-phenyl-propionicacid; or a pharmaceutically acceptable salt thereof.
 10. The method ofclaim 1 wherein the PTPase inhibiting compound is selected from thegroup of:(2S)-2-[4-(9-Bromo-2-,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionicacid;{(2R)-2-[4-(2,3-Dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionylamino}-aceticacid;(R)-2-[4-(9-Bromo-2-,3-dimethyl-naphtho[2,3-b]furan-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionicacid;(R)-2-[2-Cyclopentyl-4-(2-,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-propionicacid;(R)-2-[4-(9-Bromo-2-,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenoxy]-propionicacid; or a pharmaceutically acceptable salt thereof.
 11. The method ofclaim 1 wherein the PTPase inhibiting compound is selected from thegroup of:(R)-2-[4-(2-,3-Dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-ethyl-phenoxy]-3-phenyl-propionicacid; 2-Bromo-4-(2-,3-dimethyl-naphtho[2,3-b]furan-4-yl)-6-ethyl-phenol;(R)-2-[2-Bromo-4-(2-,3-dimethyl-naphtho[2,3-b]furan-4-yl)-6-ethyl-phenoxy]-3-phenyl-propionicacid;(R)-2-[4-(9-Bromo-2-,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-propyl-phenoxy]-3-phenyl-propionicacid;(2R)-2-[4-(9-Bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phenoxy]-3-phenyl-propionicacid; or a pharmaceutically acceptable salt thereof.
 12. The method ofclaim 1 wherein the biguanide agent is metformin, or a pharmaceuticallyacceptable salt thereof.
 13. The method of claim 1 wherein the optionalsulfonylurea agent is selected from group of glyburide, glyburide,glipizide, glimepiride, chlorpropamide, tolbutamide, or tolazamide, or apharmaceutically acceptable salt form thereof.
 14. A method of treatingmetabolic disorders mediated by insulin resistance or hyperglycemia in amammal, the method comprising administering to a mammal in need thereofa pharmaceutically effective amount of a pharmaceutically effectiveamount of a PTPase inhibiting compound, as described in claim 1, apharmaceutically effective amount of a biguanide agent and, optionally,a sulfonylurea agent and or a pharmaceutically acceptable salt thereof.15. The method of claim 14 wherein the biguanide agent is metformin, ora pharmaceutically acceptable salt thereof.
 16. The method of claim 14wherein the optional sulfonylurea agent is selected from group ofglyburide, glyburide, glipizide, glimepiride, chlorpropamide,tolbutamide, or tolazamide, or a pharmaceutically acceptable salt formthereof.
 17. The method of claim 14 wherein the PTPase inhibitingcompound is(2R)-2-[4-(9-Bromo-2,3-dimethyl-naptho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionicacid, or(R)-2-[2,6-Dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]3-phenyl-propionicacid, or(R)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionicacid, or a pharmaceutically acceptable salt form thereof.
 18. A methodof modulating blood glucose levels in a mammal, the method comprisingadministering to a mammal in need thereof a pharmaceutically effectiveamount of a pharmaceutically effective amount of a PTPase inhibitingcompound, as described in claim 1, a pharmaceutically effective amountof a biguanide agent and, optionally, a sulfonylurea agent and or apharmaceutically acceptable salt thereof.
 19. The method of claim 18wherein the biguanide agent is metformin, or a pharmaceuticallyacceptable salt thereof.
 20. The method of claim 18 wherein the optionalsulfonylurea agent is selected from group of glyburide, glyburide,glipizide, glimepiride, chlorpropamide, tolbutamide, or tolazamide, or apharmaceutically acceptable salt form thereof.
 21. The method of claim18 wherein the PTPase inhibiting compound is(2R)-2-[4-(9-Bromo-2,3-dimethyl-naptho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionicacid, or(R)-2-[2,6-Dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]3-phenyl-propionicacid, or(R)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionicacid, or a pharmaceutically acceptable salt form thereof.
 22. Apharmaceutical composition comprising a pharmaceutically acceptablecarrier or excipient and: a) a pharmaceutically effective amount ofmetformin, or a pharmaceutically acceptable salt thereof; and b) apharmaceutically effective amount of a PTPase inhibiting compound ofclaim 1, or a pharmaceutically acceptable salt form thereof; and c)optionally, a pharmaceutically effective amount of a sulfonylurea agent.23. The pharmaceutical composition of claim 22 comprising apharmaceutically acceptable carrier or excipient and: a) apharmaceutically effective amount of metformin, or a pharmaceuticallyacceptable salt thereof; and b) a pharmaceutically effective amount of(2R)-2-[4-(9-Bromo-2,3-dimethyl-naptho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionicacid, or(R)-2-[2,6-Dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]3-phenyl-propionicacid, or(R)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]-thiophen-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionicacid, or a pharmaceutically acceptable salt form thereof; and c)optionally, a pharmaceutically effective amount of a sulfonylurea agentselected from the group of glyburide, glyburide, glipizide, glimepiride,chlorpropamide, tolbutamide, or tolazamide, or a pharmaceuticallyacceptable salt form thereof.